Pancreatic cancer is suppressed by fibroblast-derived collagen I

Clinical implementation of anti-stromal therapies in pancreatic cancer has been delayed by unanticipated tumor-restraining properties the desmoplastic stroma. In confronting these challenges, Chen et al. demonstrate this issue Cancer Cell that fibroblast-specific deletion collagen I, background oncogenic Kras-induced spontaneous murine ductal adenocarcinoma, enhances immune suppression and accelerates progression disease. Pancreatic adenocarcinoma (PDAC) belongs to most aggressive group solid tumors humans, a dismal overall 5-year survival rate below 8% (Hessmann al., 2020Hessmann E. Buchholz S.M. Demir I.E. Singh S.K. Gress T.M. Ellenrieder V. Neesse A. Microenvironmental Determinants Cancer.Physiol. Rev. 2020; 100: 1707-1751Crossref PubMed Scopus (52) Google Scholar). Patients are often diagnosed with locally advanced or metastatic disease, only 15%–20% patients have surgically resectable tumors. Systemic chemotherapy is therefore treatment option for PDAC. A histological hallmark PDAC dense highly complex stroma, made up stromal cells including cancer-associated fibroblasts (CAFs) cells, embedded dense, collagen-rich extracellular matrix (ECM). The compressed stroma creates hypo-vascular environment increased interstitial fluid pressure compromises drug delivery consequently leads therapy resistance As consequence, intense research efforts focused on developing support ameliorate efficacy chemotherapeutics. Despite multiple successful preclinical studies, none approved so far. This setback can be linked having both tumor-promoting Functionally, one consider double-edged sword. On hand, biomechanical ECM nurture tumorigenesis stimulating proliferation, migration, metastasis. led several studies demonstrating specific targeting ECM-remodeling (i.e., crosslinking) mechanosignaling pathways FAK ROCK signaling) improve (Jiang 2016Jiang H. Hegde S. Knolhoff B.L. Zhu Y. Herndon J.M. Meyer M.A. Nywening Hawkins W.G. Shapiro I.M. Weaver D.T. al.Targeting focal adhesion kinase renders cancers responsive checkpoint immunotherapy.Nat. Med. 2016; 22: 851-860Crossref (480) Scholar; Laklai 2016Laklai Miroshnikova Y.A. Pickup M.W. Collisson E.A. Kim G.E. Barrett A.S. Hill R.C. Lakins J.N. Schlaepfer D.D. Mouw J.K. al.Genotype tunes tissue tension induce matricellular fibrosis tumor progression.Nat. 497-505Crossref (301) Miller 2015Miller B.W. Morton J.P. Pinese M. Saturno G. Jamieson N.B. McGhee Timpson P. Leach J. McGarry L. Shanks LOX/hypoxia axis reverses many features make deadly: inhibition LOX abrogates metastasis efficacy.EMBO Mol. 2015; 7: 1063-1076Crossref (160) Vennin 2017Vennin C. Chin V.T. Warren S.C. Lucas M.C. Herrmann D. Magenau Melenec Walters S.N. Del Monte-Nieto Conway J.R. al.Australian Genome Initiative (APGI)Transient priming via uncouples progression, sensitivity chemotherapy, metastasis.Sci. Transl. 2017; 9: eaai8504Crossref (147) other non-selective depletion Hedgehog signaling depleting αSMA-positive more poorly differentiated deprived content reduced (Özdemir 2014Özdemir B.C. Pentcheva-Hoang T. Carstens J.L. Zheng X. Wu C.C. Simpson T.R. Sugimoto Kahlert Novitskiy S.V. al.Depletion carcinoma-associated induces immunosuppression pancreas survival.Cancer Cell. 2014; 25: 719-734Abstract Full Text PDF (1241) Rhim 2014Rhim A.D. Oberstein P.E. Thomas D.H. Mirek E.T. Palermo C.F. Sastra S.A. Dekleva E.N. Saunders Becerra C.P. Tattersall I.W. al.Stromal elements act restrain, rather than support, adenocarcinoma.Cancer 735-747Abstract (1163) These findings supported paradoxical acceleration some who receive inhibitors observations imply accommodates properties, they highlight need further investigations prior clinical implementation. Stromal maintain homeostasis through continuous synthesis remodeling collagens components. Collagen architecture strongly altered during development estimated comprise 90% total mass human Most prominent fibrillar collagens, which constitute majority (Tian 2019Tian Clauser K.R. Öhlund Rickelt Huang Gupta Mani D.R. Carr Tuveson D.A. Hynes R.O. Proteomic analyses reveal different contributions cells.Proc. Natl. Acad. Sci. USA. 2019; 116: 19609-19618Crossref (97) To elucidate role I PDAC, took advantage dual-recombinase technique combines Flp-FRT recombinase Cre-loxP system delete αSMA-expressing fibroblasts, combination K-Ras loss p53 epithelial cells. They first developed FSF-KrasG12D/+;Trp53frt/frt;Pdx1-Flp (KPPF) mouse, reminiscent classical LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) model, then FSF-KrasG12D/+;Trp53frt/frt;Pdx1-Flp;αSMA-Cre;Col1a1loxP/loxP (KPPF;Col1smaKO) mouse collagen-1a1 (Chen 2021Chen Yang Wang C.-J. LeBleu V.S. Kalluri R. Type αSMA+ myofibroblasts alters intratumoral landscape cancer.Cancer 2021; 39Google Single-cell RNA sequencing (scRNA-seq) unfractionated KPPF determined principal cell type expresses αSMA I. scRNA-seq analysis also confirmed presence three CAF populations (myCAF, iCAF, apCAF) demonstrated myCAF produces transcripts, although iCAF apCAF express significant amount context development, ~50% reduction without any compensatory upregulation collagens. KPPF;Col1smaKO were accompanied decreased desmoplasia-associated markers biophysical stiffness. Interestingly, accelerated significantly survival. At endpoint, associated undifferentiated invasive phenotype (Figure 1). revealed no major differences number cluster distribution among endothelial granulocytes, two models. Likewise, blood vessel density, pericyte coverage, vascular integrity could detected contrary, displayed increasing numbers CD206+/F4/80+/Arg1+/CCL2+/interleukin-18+ myeloid-derived suppressor (MDSCs), suppressed recruitment B T lymphocytes at early late stages went expressed high levels cytokines, IL-18, CCL2, CXCL5, known polarization MDSCs ScRNA-seq Il18 Ccl2 produced MDSCs, whereas Cxcl5 Mechanistically, was suggested regulate SOX9-driven expression create an immune-suppressive devoid CD8+ Importantly, treating mice against CXCL5-CXCR2 (CXCR2 inhibitor, SB-225002) CCL2-CCR2 (CCR2 RS-504393), improved animal means normalizing observed control mice. had minimal effect mice, suggesting collagen-poor correlates environment. validated hypothesis small cohort samples (n = 108) positive correlation between CD4+ FoxP3- effector (Teffs), but not FoxP3+ regulatory (Tregs). brief, suggest functionally CD206+/F4/80+/Arg1+ MDSC may contain low content. agreement show fibrolytic (αSMAhigh/collagen-Ilow), exhibiting CD206+ macrophages lower worse median progression-free (Mahajan 2018Mahajan U.M. Langhoff Goni Costello Greenhalf W. Halloran Ormanns Kruger Boeck Ribback al.Immune Signature Associated With Progression-Free Survival Resected Ductal Adenocarcinoma.Gastroenterology. 2018; 155: 1625-1639.e1622Abstract (92) results consistent previous reports showing ablation point prognoses Özdemir discovery heterogeneous it will now important thoroughly characterize each population their properties. Conversely, neglect tumor-derived ECM, highlighted recent proteomic tumors, elegantly demonstrates components from tend poor patient survival, fibroblast-derived positively negatively correlated It tempting model stromal-derived reaction initially aims suppress transformation eventually becomes tumor-promoting, because begin manipulate ECM. Indeed, elucidating complexity certainly continue astonish scientists future. work Ragnar Söderberg Foundation ( N91/15 , CDM), Cancerfonden CAN 2016/783 2018/230 19 0632 Pj ), Swedish Research Council 2017-03389 2020-02088 Crafoord 20160782 20171049 Åke Wiberg M16-0120 M17-0235 Ollie Elof Ericssons . author declares competing interests. augments cancerChen al.Cancer CellMarch 4, 2021In BriefChen identify (Col1) using models decreases Col1 cancer. promotes CD206+F4/80+ARG1+ attenuated combined CXCR2 CCR2. Full-Text