Oncogenic collagen I homotrimers from cancer cells bind to α3β1 integrin and impact tumor microbiome and immunity to promote pancreatic cancer

Chen, Yang; Yang, Stephen C.; Tavormina, Jena; Tampe, Désirée; Zeisberg, Michael; Wang, Huamin; Mahadevan, Krishnan K.; Wu, Chang-Jiun; Sugimoto, Hikaru; Chang, Chia‐Chi; Jenq, Robert R.; McAndrews, Kathleen M.; Kalluri, Raghu

doi:10.1016/j.ccell.2022.06.011

Cited by 122 publications

(91 citation statements)

References 60 publications

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“…As we have shown that eliminating collagen from tumor cells disrupts oncostream structure, we propose that doing so pharmacologically may be a potential novel therapy. Interestingly, similar production of Collagen 1 by tumor cells has recently been shown in pancreatic cancer (16). Though there have not yet been clinical trials in GBM tumors targeting the ECM, such trials have been performed in pancreatic cancer (17,18).…”

Section: Introductionmentioning

confidence: 70%

“…Chen et al. identified that type I collagen produced by pancreatic cancer cells is the abnormal oncogenic homotrimer variant and its deletion in cancer cells inhibit tumor progression and enriches T cells with enhanced efficacy of anti-PD1 immunotherapy ( 16 ). We recently demonstrated that inhibition of COL1A1 expression within the GBM tumor cells reprogramed the tumoral microenvironment and inhibited tumor invasion and progression ( 15 ).…”

Section: Therapeutic Opportunities Targeting the Extracellular Matrix...mentioning

confidence: 99%

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The complex interactions between the cellular and non-cellular components of the brain tumor microenvironmental landscape and their therapeutic implications

et al. 2022

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Glioblastoma (GBM), an aggressive high-grade glial tumor, is resistant to therapy and has a poor prognosis due to its universal recurrence rate. GBM cells interact with the non-cellular components in the tumor microenvironment (TME), facilitating their rapid growth, evolution, and invasion into the normal brain. Herein we discuss the complexity of the interactions between the cellular and non-cellular components of the TME and advances in the field as a whole. While the stroma of non-central nervous system (CNS) tissues is abundant in fibrillary collagens, laminins, and fibronectin, the normal brain extracellular matrix (ECM) predominantly includes proteoglycans, glycoproteins, and glycosaminoglycans, with fibrillary components typically found only in association with the vasculature. However, recent studies have found that in GBMs, the microenvironment evolves into a more complex array of components, with upregulated collagen gene expression and aligned fibrillary ECM networks. The interactions of glioma cells with the ECM and the degradation of matrix barriers are crucial for both single-cell and collective invasion into neighboring brain tissue. ECM-regulated mechanisms also contribute to immune exclusion, resulting in a major challenge to immunotherapy delivery and efficacy. Glioma cells chemically and physically control the function of their environment, co-opting complex signaling networks for their own benefit, resulting in radio- and chemo-resistance, tumor recurrence, and cancer progression. Targeting these interactions is an attractive strategy for overcoming therapy resistance, and we will discuss recent advances in preclinical studies, current clinical trials, and potential future clinical applications. In this review, we also provide a comprehensive discussion of the complexities of the interconnected cellular and non-cellular components of the microenvironmental landscape of brain tumors to guide the development of safe and effective therapeutic strategies against brain cancer.

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Section: Introductionmentioning

confidence: 70%

Section: Therapeutic Opportunities Targeting the Extracellular Matrix...mentioning

confidence: 99%

The complex interactions between the cellular and non-cellular components of the brain tumor microenvironmental landscape and their therapeutic implications

et al. 2022

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“…Indeed, it has been observed that a linearized and perpendicular disposition of collagen fibers confers a higher invasiveness capacity in breast cancer cells [ 132 ]. In a preclinical model of pancreatic cancer, it has been shown that cancer-secreted type I collagen homotrimers interact with a3b1 integrin on cancer cells promoting cell pro-survival and proliferative signaling cascades, and their inhibition leads to increased tumoral T cell infiltration and enhanced anti-cancer responses upon anti-PD1 immunotherapy [ 133 ]. Integrin targeting, either directly or by interfering with downstream effectors (i.e., Src and FAK) is currently also being investigated in combination with ICB [ 126 ].…”

Section: Targeting Immune System In Cancermentioning

confidence: 99%

Targeting Cellular Components of the Tumor Microenvironment in Solid Malignancies

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Antonarelli

Repetto

et al. 2022

Cancers

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Cancers are composed of transformed cells, characterized by aberrant growth and invasiveness, in close relationship with non-transformed healthy cells and stromal tissue. The latter two comprise the so-called tumor microenvironment (TME), which plays a key role in tumorigenesis, cancer progression, metastatic seeding, and therapy resistance. In these regards, cancer-TME interactions are complex and dynamic, with malignant cells actively imposing an immune-suppressive and tumor-promoting state on surrounding, non-transformed, cells. Immune cells (both lymphoid and myeloid) can be recruited from the circulation and/or bone marrow by means of chemotactic signals, and their functionality is hijacked upon arrival at tumor sites. Molecular characterization of tumor-TME interactions led to the introduction of novel anti-cancer therapies targeting specific components of the TME, such as immune checkpoint blockers (ICB) (i.e., anti-programmed death 1, anti-PD1; anti-Cytotoxic T-Lymphocyte Antigen 4, anti-CTLA4). However, ICB resistance often develops and, despite the introduction of newer technologies able to study the TME at the single-cell level, a detailed understanding of all tumor-TME connections is still largely lacking. In this work, we highlight the main cellular and extracellular components of the TME, discuss their dynamics and functionality, and provide an outlook on the most relevant clinical data obtained with novel TME-targeting agents, with a focus on T lymphocytes, macrophages, and cancer-associated fibroblasts.

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“…A recent study published in Cancer Cell reported a novel role of type I collagen (Col1)–α3β1 integrin signaling axis in the pathogenesis of pancreatic ductal adenocarcinoma (PDAC), suggesting that pancreatic cancer cells expressed Col1 homotrimer as the potential of the therapeutic target 1 . They found that homotrimer of Col1, an abnormal variant produced by pancreatic cancer cells, had a great impact on the development of PDAC, while the deletion of variant induced enrichment of tumor microbiome and boost immune response, eventually resulting in the inhibition of tumor progression (Figure 1).…”

Section: Figurementioning

confidence: 99%

Type I collagen homotrimers: A potential cancer‐specific interventional target

et al. 2022

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Pancreatic cancer cell‐derived homotrimer type 1 collagen plays an important role in the pathogenesis of pancreatic cancer. Homotrimer type 1 collagen produced by pancreatic cancer cells upregulated proliferation‐related pathways through the integrin α3β1 axis. Deletion of homotrimer type 1 collagen in genetically engineered mouse models altered the intratumoral microbiome, increased T‐cell infiltration, enhanced anti‐PD‐1 therapy, and ultimately inhibited tumor growth.

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Oncogenic collagen I homotrimers from cancer cells bind to α3β1 integrin and impact tumor microbiome and immunity to promote pancreatic cancer

Cited by 122 publications

References 60 publications

The complex interactions between the cellular and non-cellular components of the brain tumor microenvironmental landscape and their therapeutic implications

The complex interactions between the cellular and non-cellular components of the brain tumor microenvironmental landscape and their therapeutic implications

Targeting Cellular Components of the Tumor Microenvironment in Solid Malignancies

Type I collagen homotrimers: A potential cancer‐specific interventional target

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