Reshaping the Tumor Stroma for Treatment of Pancreatic Cancer

Pancreatic cancer is accompanied by a fibrotic reaction that alters interactions between tumor cells and the stroma to promote tumor progression. Consequently, strategies to target the tumor stroma might be used to treat patients with pancreatic cancer. We review recently developed approaches for reshaping the pancreatic tumor stroma and discuss how these might improve patient outcomes. We also describe relationships between the pancreatic tumor extracellular matrix, the vasculature, the immune system, and metabolism, and discuss the implications for the development of stromal compartment−specific therapies. Pancreatic cancer is accompanied by a fibrotic reaction that alters interactions between tumor cells and the stroma to promote tumor progression. Consequently, strategies to target the tumor stroma might be used to treat patients with pancreatic cancer. We review recently developed approaches for reshaping the pancreatic tumor stroma and discuss how these might improve patient outcomes. We also describe relationships between the pancreatic tumor extracellular matrix, the vasculature, the immune system, and metabolism, and discuss the implications for the development of stromal compartment−specific therapies. Pancreatic cancer is predicted to be the second-largest cause of cancer-related deaths by 2030 and <7% of patients survive for 5 years.1Rahib L. Smith B.D. Aizenberg R. et al.Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States.Cancer Res. 2014; 74: 2913-2921Crossref PubMed Scopus (884) Google Scholar We therefore need to identify new therapeutic targets and radically rethink our approach to developing treatments for patients with pancreatic cancer. Pancreatic cancer progression is accompanied by a fibrotic stromal (desmoplastic) reaction characterized by extensive deposition of extracellular matrix (ECM) components, recruitment and activation of cancer-associated fibroblasts (CAFs), decreased vasculature patency, and altered immune-surveillance.2Sinha S. Leach S.D. New insights in the development of pancreatic cancer.Curr Opin Gastroenterol. 2016 Jul 21; ([Epub ahead of print])Crossref PubMed Scopus (2) Google Scholar, 3Kleeff J. Korc M. Apte M. et al.Pancreatic cancer.Nat Rev Dis Primers. 2016; 2: 16022Crossref PubMed Google Scholar Stromal remodeling leads to altered interactions between tumor cells and stromal compartments, which can promote tumor progression.4Pickup M.W. Mouw J.K. Weaver V.M. The extracellular matrix modulates the hallmarks of cancer.EMBO Rep. 2014; 15: 1243-1253Crossref PubMed Scopus (213) Google Scholar Studies have shown that the stroma can promote and prevent pancreatic cancer progression, highlighting that multiple considerations should be taken into account when clinically translating stromal-based therapies.5Cox T. Erler J. Fibrosis and cancer: partner in crime or opposing forces?.Trends in Cancer. 2016; 2: 279-282Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar We review the importance of the different stromal compartments, strategies for targeting them or reshaping the pancreatic tumor stroma, and we explore their potential to improve outcomes in patients with pancreatic cancer. In particular, we outline how short-term, fine-tuned manipulation of interactions between cancer cells and the stroma, both in primary and metastatic sites (such as the liver), can improve the efficacy of chemotherapy and reduce growth of metastases, while maintaining normal tissue functions. We discuss findings from studies reporting the intricate interactions between different elements of the stroma (such as the ECM, CAFs, immune cells, blood, and the lymphatic vasculature), and how these affect the development of new stromal-based treatments for pancreatic cancer. We also summarize recently developed diagnostic tools and preclinical models that can be used to assess individualized stromal-based therapies. Lastly, we discuss how discoveries from research on other types of tumors with high levels of fibrosis could be repurposed in pancreatic cancer. Within pancreatic tumors, extensive remodeling of the ECM can increase tissue stiffness to mechanically induce intracellular signaling that promotes disease progression.6Humphrey J.D. Dufresne E.R. Schwartz M.A. Mechanotransduction and extracellular matrix homeostasis.Nat Rev Mol Cell Biol. 2014; 15: 802-812Crossref PubMed Scopus (252) Google Scholar Remodeling of the ECM does not occur evenly throughout the tumor—it was recently shown to be heterogeneous and spatially well defined within pancreatic tumor tissues and to correlate with clinical and pathology features of patient tumors.7Laklai H. Miroshnikova Y.A. Pickup M.W. et al.Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression.Nat Med. 2016; 22: 497-505Crossref PubMed Scopus (245) Google Scholar Although ECM remodeling has been proposed to be predominantly mediated by activated stromal cells, such as CAFs,8Kalluri R. The biology and function of fibroblasts in cancer.Nat Rev Cancer. 2016; 16: 582-598Crossref PubMed Scopus (129) Google Scholar cancer cell tension, mediated for instance by JAK signaling via STAT and Rho kinase (ROCK), can tune the pancreatic ECM and thereby mechanically activate signaling pathways that regulate survival and metastasis in pancreatic cancer cells.7Laklai H. Miroshnikova Y.A. Pickup M.W. et al.Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression.Nat Med. 2016; 22: 497-505Crossref PubMed Scopus (245) Google Scholar, 9Wormann S.M. Song L. Ai J. et al.Loss of P53 function activates JAK2-STAT3 signaling to promote pancreatic tumor growth, stroma modification, and gemcitabine resistance in mice and is associated with patient survival.Gastroenterology. 2016; 151: 180-193e12Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Similarly, increased stiffening of the ECM has been reported to promote the epithelial−mesenchymal transition in pancreatic tumor cells, a key step of the metastatic cascade, and to reduce their response to chemotherapy,10Rice A.J. Cortes E. Lachowski D. et al.Matrix stiffness induces epithelial-mesenchymal transition and promotes chemoresistance in pancreatic cancer cells.Oncogenesis. 2017; 6: e352Crossref PubMed Scopus (5) Google Scholar, 11Horejs C.M. St-Pierre J.P. Ojala J.R.M. et al.Preventing tissue fibrosis by local biomaterials interfacing of specific cryptic extracellular matrix information.Nat Commun. 2017; 8: 15509Crossref PubMed Scopus (0) Google Scholar, 12Krebs A.M. Mitschke J. Lasierra Losada M. et al.The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer.Nat Cell Biol. 2017; 19: 518-529Crossref PubMed Scopus (36) Google Scholar The mechanical features of the ECM can determine pancreatic cancer aggressiveness. Consequently, disruption of the mechanical feedback between tumor cells and the ECM, or mechano-reciprocity,6Humphrey J.D. Dufresne E.R. Schwartz M.A. Mechanotransduction and extracellular matrix homeostasis.Nat Rev Mol Cell Biol. 2014; 15: 802-812Crossref PubMed Scopus (252) Google Scholar has been evaluated as an approach to impair pancreatic cancer progression. Initial studies assessing ECM targeting have demonstrated that reducing fibrosis in pancreatic tumors is possible by inhibiting the fibrotic Hedgehog signaling pathway13Olive K.P. Jacobetz M.A. Davidson C.J. et al.Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer.Science. 2009; 324: 1457-1461Crossref PubMed Scopus (1512) Google Scholar or by targeting hyaluronic acid (HA) with pegylated hyaluronidase (PEGPH20)14Provenzano P.P. Cuevas C. Chang A.E. et al.Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma.Cancer Cell. 2012; 21: 418-429Abstract Full Text Full Text PDF PubMed Scopus (631) Google Scholar, 15Jacobetz M.A. Chan D.S. Neesse A. et al.Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer.Gut. 2013; 62: 112-120Crossref PubMed Scopus (292) Google Scholar in Pdx1-cre; KrasG12D; p53fl/+ (KPC) mice bearing primary tumors.16Hingorani S.R. Petricoin E.F. Maitra A. et al.Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse.Cancer Cell. 2003; 4: 437-450Abstract Full Text Full Text PDF PubMed Scopus (1152) Google Scholar, 17Hingorani S.R. Wang L. Multani A.S. et al.Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice.Cancer Cell. 2005; 7: 469-483Abstract Full Text Full Text PDF PubMed Scopus (893) Google Scholar These strategies led to reduced intra-tumor pressure, increased vasculature patency, and longer survival times of KPC mice. The efficacy of anti-ECM agents in combination with chemotherapy has also been assessed in clinical trials for pancreatic cancer. For instance, vismodegib, IPI-926 (hedgehog inhibitors, NSC74769,18Catenacci D.V. Junttila M.R. Karrison T. et al.Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer.J Clin Oncol. 2015; 33: 4284-4292Crossref PubMed Scopus (60) Google Scholar and NCT0138353819Ko A.H. LoConte N. Tempero M.A. et al.A phase I study of FOLFIRINOX Plus IPI-926, a Hedgehog pathway inhibitor, for advanced pancreatic adenocarcinoma.Pancreas. 2016; 45: 370-375Crossref PubMed Scopus (26) Google Scholar), or PEGPH20 (NCT01839487,20Hingorani S.R. Harris W. Hendifar A. et al.High response rate and PFS with PEGPH20 added to nab-paclitaxel/gemcitabine in stage IV previously untreated pancreatic cancer patients with high-HA tumors: interim results of a randomized phase II study.J Clin Oncol. 2015; 33 (Abstract 4006)Google Scholar Table 1) have been tested in combination with chemotherapy. PEGPH20 is also currently being tested in patients where high HA deposition in their tumors is assessed as a marker for response to treatment (HaLo 109-202, Table 1). The promising interim results from these trials led to a phase 3 trial for PEGPH20 in combination with gemcitabine and abraxane (NCT02715804, HaLo 301). In addition, a phase 1b/2 study of PEGPH20 in combination with anti-PDL1 cancer immunotherapy is underway21Wong K.M. Horton K.J. Coveler A.L. et al.Targeting the tumor stroma: the biology and clinical development of pegylated recombinant human hyaluronidase (PEGPH20).Curr Oncol Rep. 2017; 19: 47Crossref PubMed Scopus (6) Google Scholar (Table 1).Table 1Clinical Trials in Pancreatic Cancer Assessing Stroma ManipulationTargetDrugCombinationPatientsTrial phaseStatusNIH numberCXCR2MEDI4736Gemcitabine, nab-paclitaxel, or AZD5069Stage IV PDACI/IIRecruitingNCT02583477Cancer cell metabolismMetformin and standardized dietary supplementsaDietary supplements include curcumin, vitamin D, vitamin K-2, vitamin K-1, B-6, high selenium broccoli sprouts, epigallocatechin gallate, l-carnitine, garlic extract, genistein, zinc amino chelate, mixed toxopherols, ascorbic acid, and d-limoneneGemcitabine, nab-paclitaxelPDACNonresectableIRecruitingNCT02336087Vitamin D metabolic pathwayParicalcitolGemcitabine, nab-paclitaxelNeoadjuvant settings for resectable PCIOngoingNCT02030860Study of the relationship between serum 25-hydroxyvitamin D and overall survivalAdvanced PCCompleted (awaiting results)NCT01327794Macrophage activityVitamin D (EF_002)Dose escalationSolid cancersICompleted (awaiting results)NCT02052492CAFsAll-trans retinoic acidGemcitabine, nab-paclitaxelPDACIRecruitingNCT03307148 (STAR_PAC)IL-10AM0010FOLFOX, 5-FU, leucovorinSecond-line PCIIIRecruitingNCT02923921Polyamine transport uptake and metabolismSBP-101Assessment of safety and tolerabilityPCINCT02657330HA stratification of patient tumors based on HA content (high/low)PEGPH20 (HALO-109-202)Gemcitabine, nab-paclitaxelStage IVIIOngoingNCT01839487HAPEGPH20CetuximabPCIb/IICompleted (deemed safe)NCT02241187GemcitabineStage IVI/IICompleted (awaiting results)NCT01453153Gemcitabine, nab-paclitaxel, rivaroxban (anti-coagulant)PCPDACIRecruitingNCT02921022Gemcitabine, nab-paclitaxelStage IVIIIRecruitingNCT02715804Gemcitabine, radiotherapyNonresectable PDACIIOngoingNCT0291882FOLFIRINOXStage IVIb/IIOngoingNCT01959139Development of imaging toolsStudy of the ability of imaging PC stroma using DWI, DCE-MRI, and 18F-HX4-PET/CT to predict response to gemcitabineImaging combined with surgery, adjuvant chemotherapy or neoadjuvant chemotherapyPCBiomarkerRecruitingNCT01989000 (MIPA)β-adrenergic receptors, stress signalingβ-blockersPreoperativeBreastPCIIIIRecruitingACTRN12615000889550bPersonal communication with M. Diener, E. Sloan, and I. Rooman, September 2017.FAKDefactinibPD-1MesotheliomaNSCLCPCI/IIRecruitingNCT02758587DefactinibPD-1, gemcitabine, nab-paclitaxelSolid tumorsPCI /IIRecruitingNCT02546531GSK2256098TremetinibPDACIIRecruitingNCT02428270PD-1PembrolizumabParicalcitol, with or without gemcitabine, nab-paclitaxelResectable PCIRecruitingNCT02930902NivolumabIpilimumab and cobimetinibAdvanced and metastatic solid tumorsI/IIOngoingNCT01928394Colony-stimulating factor-1 receptorCabiralizumabNivolumabSolid tumorsIRecruitingNCT02526017AMG 820PembrolizumabPC, colorectal cancer, and NSCLCI/IIRecruitingNCT02713529Anti-OX40 antibodiesGSK3174998PembrolizumabSolid tumors, may be applicable in PCIRecruitingNCT02528357 (ENGAGE-1)MOXR0916AtezolizumabNeoplasmsIRecruitingNCT02410512PreoperativeGemcitabine, nab-paclitaxelNeoadjuvantOngoingNeoadjuvantOngoing2013-004200-19PRICKLEHedgehogSonidegib (LDE225)Gemcitabine, nab-paclitaxelStage IVAdvanced PCI/IIOngoing2013-002370-51 (MATRIX)HedgehogVismodegibGemcitabinePDACRecurrent PCStage IVI/IICompleted (combination not superior to cemcitabine alone)NCT01064622CT, computed tomography; DWI, diffusion weighted imaging, mean tumor apparent diffusion coefficient, DCE-MRI, dynamic contrast-enhanced magnetic resonance imaging; FOLFOX, folinic acid, fluorouracil, and oxaliplatin; FOLFIRINOX, folinic acid, fluorouracil, irinotecan, and oxaliplatin; 5-FU, 5-fluorouracil; NIH, National Institutes of Health; NSCLC, non-small cell lung cancer; PC, pancreatic cancer; PDAC, pancreatic ductal adenocarcinoma.a Dietary supplements include curcumin, vitamin D, vitamin K-2, vitamin K-1, B-6, high selenium broccoli sprouts, epigallocatechin gallate, l-carnitine, garlic extract, genistein, zinc amino chelate, mixed toxopherols, ascorbic acid, and d-limoneneb Personal communication with M. Diener, E. Sloan, and I. Rooman, September 2017. Open table in a new tab CT, computed tomography; DWI, diffusion weighted imaging, mean tumor apparent diffusion coefficient, DCE-MRI, dynamic contrast-enhanced magnetic resonance imaging; FOLFOX, folinic acid, fluorouracil, and oxaliplatin; FOLFIRINOX, folinic acid, fluorouracil, irinotecan, and oxaliplatin; 5-FU, 5-fluorouracil; NIH, National Institutes of Health; NSCLC, non-small cell lung cancer; PC, pancreatic cancer; PDAC, pancreatic ductal adenocarcinoma. Inhibition of lysyl oxidase (LOX), an enzyme required for collagen biogenesis and cross-linking, which is overexpressed in hypoxic tumor environments, was also assessed in KPC mice. In KPC mice with pancreatic primary tumors, the combination of a LOX blocking antibody with gemcitabine reduced ECM cross-linking, blocked metastasis, and increased survival times compared to gemcitabine alone.22Miller B.W. Morton J.P. Pinese M. et al.Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy.EMBO Mol Med. 2015; 7: 1063-1076Crossref PubMed Scopus (46) Google Scholar The increased efficacy of gemcitabine upon LOX inhibition was not due to increased vasculature patency or drug delivery, suggesting that manipulation of the ECM and of mechano-reciprocity using LOX inhibitors might deprive cancer cells of mechanical survival cues that promote metastasis and resistance to treatment.22Miller B.W. Morton J.P. Pinese M. et al.Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy.EMBO Mol Med. 2015; 7: 1063-1076Crossref PubMed Scopus (46) Google Scholar Interestingly, inhibition of LOX, in combination with gemcitabine in mice with locally advanced tumors with a well-established matrix, did not significantly increase survival.22Miller B.W. Morton J.P. Pinese M. et al.Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy.EMBO Mol Med. 2015; 7: 1063-1076Crossref PubMed Scopus (46) Google Scholar As LOX inhibition blocks only progressive cross-linking of the ECM and does not reverse previous LOX-induced changes to the ECM, these findings indicate that agents to manipulate the ECM are likely to have tumor stage−dependent effects. In light of this, ECM biomarkers could be used to identify tumors most likely to respond to these agents. Studies of stroma-targeting agents in mouse models of pancreatic tumors have mainly been tested in mice with early-stage (primary) tumors, and have provided insights into the effects of long-term stromal manipulation.14Provenzano P.P. Cuevas C. Chang A.E. et al.Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma.Cancer Cell. 2012; 21: 418-429Abstract Full Text Full Text PDF PubMed Scopus (631) Google Scholar, 15Jacobetz M.A. Chan D.S. Neesse A. et al.Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer.Gut. 2013; 62: 112-120Crossref PubMed Scopus (292) Google Scholar, 23Rhim A.D. Oberstein P.E. Thomas D.H. et al.Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma.Cancer Cell. 2014; 25: 735-747Abstract Full Text Full Text PDF PubMed Scopus (458) Google Scholar, 24Ozdemir B.C. Pentcheva-Hoang T. Carstens J.L. et al.Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival.Cancer Cell. 2014; 25: 719-734Abstract Full Text Full Text PDF PubMed Scopus (462) Google Scholar, 25Chauhan V.P. Martin J.D. Liu H. et al.Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels.Nat Commun. 2013; 4: 2516Crossref PubMed Scopus (192) Google Scholar However, most patients present with late-stage pancreatic cancer and metastases. Consequently, there are valid arguments for testing anti-stromal agents in mice with early- or late-stage tumors to optimize stromal agents in combination with standard-of-care therapies in both settings26Steeg P.S. Targeting metastasis.Nat Rev Cancer. 2016; 16: 201-218Crossref PubMed Scopus (129) Google Scholar, 27Yachida S. Jones S. Bozic I. et al.Distant metastasis occurs late during the genetic evolution of pancreatic cancer.Nature. 2010; 467: 1114-1117Crossref PubMed Scopus (1222) Google Scholar (Figure 1A). In addition, studies using human pancreatic tumor tissues and mathematical modeling have shown that these tumors do not always progress in a linear or gradual manner, but rather can be a result of fast and simultaneous accumulation of genetic alterations that lead to early dissemination of tumor cells.28Notta F. Chan-Seng-Yue M. Lemire M. et al.A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns.Nature. 2016; 538: 378-382Crossref PubMed Scopus (54) Google Scholar This finding suggests that testing anti-stromal agents in mice with localized primary tumors and with metastatic tumors, rather than optimizing the timing of anti-stromal agent administration, could be beneficial. Tissue stiffening is also mediated by cell contractility, which is regulated in part by ROCK signaling.29Chin V.T. Nagrial A.M. Chou A. et al.Rho-associated kinase signalling and the cancer microenvironment: novel biological implications and therapeutic opportunities.Expert Rev Mol Med. 2015; 17: e17Crossref PubMed Scopus (5) Google Scholar, 30Whatcott C.J. Ng S. Bearrett M. et al.Inhibition of ROCK1 kinase modulates both tumor cells and stromal fibroblasts in pancreatic cancer.PLoS One. 2017; 12: e0183871Crossref PubMed Scopus (0) Google Scholar, 31Holvoet T. Devriese S. Castermans K. et al.Treatment of intestinal fibrosis in experimental inflammatory bowel disease by the pleiotropic actions of a local rho kinase inhibitor.Gastroenterology. 2017; 153: 1054-1067Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Expression of ROCK1 and ROCK2 were recently found to be increased in human pancreatic tumors with stage and grade, and genomic alterations in ROCK1 and ROCK2 correlated with shorter survival times of patients.32Rath N. Morton J.P. Julian L. et al.ROCK signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growth.EMBO Mol Med. 2017; 9: 198-218Crossref PubMed Scopus (10) Google Scholar Interestingly, ROCK2 activation in noninvasive pancreatic cancer cells promoted their invasion of a collagen matrix and increased ECM remodeling, potentially via an increased release of matrix metalloproteinases (MMPs) into the surrounding environment.32Rath N. Morton J.P. Julian L. et al.ROCK signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growth.EMBO Mol Med. 2017; 9: 198-218Crossref PubMed Scopus (10) Google Scholar In line with this, short-term inhibition of ROCK activity, via oral administration of fasudil as a priming agent before administration of a chemotherapeutic, reduced fibrosis in pancreatic tumors.33Vennin C. Chin V.T. Warren S.C. et al.Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis.Sci Transl Med. 2017; 9Crossref PubMed Scopus (13) Google Scholar Intravital imaging analyses of single cells in primary and metastatic pancreatic tumors showed that pulsed and iterative priming with fasudil, rather than chronic exposure to anti-ECM drugs (Figure 1B), reduced ECM cross-linking, increased vasculature patency, and enhanced the effects of chemotherapeutic agents.33Vennin C. Chin V.T. Warren S.C. et al.Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis.Sci Transl Med. 2017; 9Crossref PubMed Scopus (13) Google Scholar Survival and proliferative stimuli provided by the ECM are partly mediated by integrins and Src signaling, and these were also reduced in tumors primed with fasudil. Src can promote progression of pancreatic tumors by reducing their responses to chemotherapy34Yeatman T.J. A renaissance for SRC.Nat Rev Cancer. 2004; 4: 470-580Crossref PubMed Google Scholar and increasing their invasive activities.35Erami Z. Herrmann D. Warren S.C. et al.Intravital FRAP imaging using an E-cadherin-GFP mouse reveals disease- and drug-dependent dynamic regulation of cell-cell junctions in live tissue.Cell Rep. 2016; 14: 152-167Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar As fasudil priming reduces Src activity, anti-stromal priming agents such as these could potentially be employed as an anti-invasive approach in pancreatic cancer. This is in line with recent assessment of Src inhibition post-surgery in pancreatic cancer.36Evans T. Van Cutsem E. Moore M. et al.Dasatinib combined with gemcitabine (Gem) in patients (pts) with locally advanced pancreatic adenocarcinoma (PaCa): CA180-375, double-blind phase II trial.J Clin Oncol. 2012 30; 15: TPS4134Google Scholar, 37Morton J.P. Karim S.A. Graham K. et al.Dasatinib inhibits the development of metastases in a mouse model of pancreatic ductal adenocarcinoma.Gastroenterology. 2010; 139: 292-303Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar Fine-tuned ROCK inhibition also reduced cancer cell resistance to shear stress in the blood circulation, decreased cancer cell seeding in the liver, and inhibited the establishment of a fibrotic environment that supports growth of metastases,33Vennin C. Chin V.T. Warren S.C. et al.Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis.Sci Transl Med. 2017; 9Crossref PubMed Scopus (13) Google Scholar as recently reported in models of melanoma.38Hirata E. Girotti M.R. Viros A. et al.Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin beta1/FAK signaling.Cancer Cell. 2015; 27: 574-588Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar Together, these findings indicate that short-term, sequential, and pulsed administration of antifibrotic agents allows subtle manipulation of the ECM and deprives cancer cells of a supportive mechanical niche.3Kleeff J. Korc M. Apte M. et al.Pancreatic cancer.Nat Rev Dis Primers. 2016; 2: 16022Crossref PubMed Google Scholar, 6Humphrey J.D. Dufresne E.R. Schwartz M.A. Mechanotransduction and extracellular matrix homeostasis.Nat Rev Mol Cell Biol. 2014; 15: 802-812Crossref PubMed Scopus (252) Google Scholar, 31Holvoet T. Devriese S. Castermans K. et al.Treatment of intestinal fibrosis in experimental inflammatory bowel disease by the pleiotropic actions of a local rho kinase inhibitor.Gastroenterology. 2017; 153: 1054-1067Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar, 33Vennin C. Chin V.T. Warren S.C. et al.Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis.Sci Transl Med. 2017; 9Crossref PubMed Scopus (13) Google Scholar This is an important advantage of fine-tuned ECM targeting because chronic, systematic ablation of fibrosis can be accompanied with enhanced metastasis and increased tumor infiltration by immune cells that support tumor progression23Rhim A.D. Oberstein P.E. Thomas D.H. et al.Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma.Cancer Cell. 2014; 25: 735-747Abstract Full Text Full Text PDF PubMed Scopus (458) Google Scholar, 24Ozdemir B.C. Pentcheva-Hoang T. Carstens J.L. et al.Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival.Cancer Cell. 2014; 25: 719-734Abstract Full Text Full Text PDF PubMed Scopus (462) Google Scholar (Figures 1B and 2A). Although remodeling of the ECM accompanies primary tumor progression, alterations of the tumor ECM can also mediate metastasis.39Peinado H. Zhang H. Matei I.R. et al.Pre-metastatic niches: organ-specific homes for metastases.Nat Rev Cancer. 2017; 17: 302-317Crossref PubMed Scopus (36) Google Scholar Changes of the ECM in distant organs before seeding of metastatic cells can be mediated by exosomes released by primary tumor cells. For instance, pancreatic cancer cell−derived exosomes can accumulate in other tissues, such as the liver, to create a premetastatic niche by activating hepatic stellate cells and Kupffer cells.39Peinado H. Zhang H. Matei I.R. et al.Pre-metastatic niches: organ-specific homes for metastases.Nat Rev Cancer. 2017; 17: 302-317Crossref PubMed Scopus (36) Google Scholar, 40Costa-Silva B. Aiello N.M. Ocean A.J. et al.Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver.Nat Cell Biol. 2015; 17: 816-826Crossref PubMed Scopus (377) Google Scholar, 41Hoshino A. Costa-Silva B. Shen T.L. et al.Tumour exosome integrins determine organotropic metastasis.Nature. 2015; 527: 329-335Crossref PubMed Scopus (535) Google Scholar This was shown to induce remodeling of the host ECM and to facilitate cancer cell invasion and growth in the liver. Surgical resection of primary tumors has also been reported to alter the ECM in other tissues, such as the lungs,42Rachman-Tzemah C. Zaffryar-Eilot S. Grossman M. et al.Blocking surgically induced lysyl oxidase activity reduces the risk of lung metastases.Cell Rep. 2017; 19: 774-784Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar and to thereby increase the ability of circulating tumor cells to form metastases at these sites compared with mice that were not undergoing surgery.42Rachman-Tzemah C. Zaffryar-Eilot S. Grossman M. et al.Blocking surgically induced lysyl oxidase activity reduces the risk of lung metastases.Cell Rep. 2017; 19: 774-784Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Given that approximately 20% of patients with pancreatic cancer are eligible for surgical resection of primary tumors, this may have implications in this disease too. In addition, local changes to the ECM in secondary organs can reawaken disseminated and dormant tumor cells (identified as single, nonproliferative tumor cells), which could then form metastases. Activation of dormant tumor cells by a fibrotic matrix can be prevented by blocking mechanical interactions between tumor cells and the ECM.43Barkan D. El Touny L.H. Michalowski A.M. et al.Metastatic growth from dormant cells induced by a col-I-enriched fibrotic environment.Cancer Res. 2010; 70: 5706-5716Crossref PubMed Scopus (142) Google Scholar Conversely, cell quiescence and dormancy can be induced by ECM components, such as lumican—further highlighting how the ECM can promote and impair tumor progression at multiple stages.44Li X. Kang Y. Roife D. et al.Prolonged exposure to extracellular lumican restrains pancreatic adenocarcinoma growth.Oncogene. 2017; 36: 5432-5438Crossref PubMed Scopus (0) Google Scholar FOXO4 was recently identified as a regulat