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Activation of adult human pancreatic ductal and ductal progenitor-like cells requires extracellular matrix protein signaling [scRNA-seq]

ABSTRACT: Ductal progenitor-like cells are a subpopulation of ductal cells in the adult human pancreas that have the potential to contribute to regenerative medicine. However, the microenvironmental cues that regulate their activation are poorly understood. Here, we establish a 3-dimensional suspension culture system containing six defined soluble factors in which primary human ductal and ductal progenitor-like cells can survive but do not proliferate. Expansion and polarization occur when cells are provided with a low concentration (5% v/v) of Matrigel, a sarcoma cell product enriched in many extracellular matrix (ECM) proteins. Screening of ECM proteins identified that collagen IV is capable of partially recapitulating the effects of Matrigel. Inhibition of integrin α1β1, a major collagen IV receptor, negates collagen IV- and Matrigel-stimulated effects. These results demonstrate that collagen IV is a key ECM protein that stimulates the expansion and polarization of human ductal and ductal progenitor-like cells via integrin α1β1 receptor signaling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE233785 | GEO | 2023/06/05

REPOSITORIES: GEO

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Project description:A major problem in cancer research is the lack of a tractable model for delayed metastasis. Herein we show that cancer cells suppressed by SISgel, a gel-forming normal ECM material derived from Small Intestine Submucosa, in flank xenografts show properties of suppression and re-activation that are very similar to normal delayed metastasis and suggest they can serve as a novel model for developing therapeutics to target micrometastases or suppressed cancer cells. Co-injection with SISgel suppressed the malignant phenotype of highly invasive J82 and T24 bladder cancer cells and highly metastatic JB-V cells in flank xenografts. Cells could remain viable up to 120 days without forming tumors and appeared much more highly differentiated and less atypical than tumors from cells co-injected with Matrigel. In 40% of SISgel xenografts, growth resumed in the malignant phenotype after a period of suppression or dormancy for at least 30 days and was more likely with implantation of 3 million cells or more cells. Ordinary Type I collagen did not suppress malignant growth, and tumors developed about as well with collagen as with Matrigel. A clear signal in gene expression over different cell lines was not seen, but in contrast, Reverse Phase Protein Analysis of 250 proteins across 4 cell lines identified a clear signal at the protein level involving Integrin Linked Kinase (ILK) signaling that was confirmed by an ILK inhibitor. We suggest that cancer cells suppressed on SISgel could serve as a model for dormancy and re-awakening to develop therapeutic targets for micrometastases. Earlier we demonstrated that the phenotype of bladder cancer cells was radically different in 3-dimensional organotypic culture when grown on a normal extracellular matrix preparation (SISgel) as compared to that observed on a cancer-modulated permissive extracellular matrix preparation (Matrigel). SISgel is a gel-forming material derived from acellular small intestine submucosa, whereas Matrigel is a basement membrane preparation obtained from a mouse sarcoma. On Matrigel the bladder cancer cells recapitulated the phenotype reported for the original tumor; in sharp contrast, most of the malignant properties were lost when the cells were grown on SISgel. Cell lines derived from papillomas formed a layered structure reminiscent of normal urothelium, whereas cell lines derived from higher grade tumors formed a noninvasive layer of cells. These findings suggested that growth of cancer cells on normal ECM could provide a model to investigate the phenomenon of suppression of malignancy by normal ECM in metastasis and recurrence. In this study we explored whether the phenotypic suppression seen in organotypic culture of bladder cancer cells on SISgel also is observed in vivo. Positive findings support the use of SISgel as a model for investigations of the dormant or suppressed tumor cell phenotype and of mechanisms by which the normal ECM exerts an inhibitory influence on tumorigenesis and metastasis. The findings strongly suggest that interactions of cancer cells with normal ECM play an important role in recurrence and metastasis and further suggest that targeting suppressed cells could represent a heretofore unexploited point of vulnerability in cancer therapy.

Project description:Col1a1 is located on mouse distal chromosome 11 (Celera 94607393-94622990bp; 15kb) and encodes type I procollagen that associates stoichiometrically with col1a2 in forming secreted type I mature collagen that self-assembles into a supramolecular fibrillar structure consisting of a protein family. Type I collagens are predominantly enriched in bone, cartilage, skin, tendons, and eye (i.e. in major fibrous tissues) making up the main extracellular matrix (ECM) component for support and scaffolding purposes. Col1a1 is known to be expressed in the embryo (E9.5; Northern dot blot), perioptic mesenchyme (E11), cornea (E11), skeleton (E14.5), brain meninges (E14.5), and cartilage (E14.5) at relatively early stages. Most evidence of type I collagen function is coupled to the latter stages of skeletal development, thus bypassing the major events of axis formation, tissue differentiation, and mesenchlymal-epithial interactions, for example, that are more symbolic of morphogens and growth factors. Members of the integrin cell surface receptor family of molecules mediate cell adhesion to ECM proteins such as collagen (mainly to type IV basement membrane collagen that forms into a polygonal meshwork), fibronectin, and laminin implicated in wound healing and inflammatory responses (e.g. Crohn disease, ulcerative colitis) in connective tissues. There is some evidence for protein-protein interactions between leukocyte-associated integrins and the interstitial matrix in promoting the migration and/or activation of extravasated leukocytes (e.g., T cells and monocytes) within the perivascular compartment, an ECM-rich environment. This region is surmised to be an important location where certain human leukocytes undergo differentiation (e.g. monocytes) and activation (neutrophils, monocytes, lymphocytes) upon extravascular migration. The von Willebrand factor (vWF), type C motif is found in various plasma proteins like complement factors, the integrins, collagen types, and other extracellular proteins. Thus, the majority of vWF-containing proteins are extracellular and a common feature appears to be involvement in multi protein complexes participating in numerous biological events (e.g. cell adhesion, migration, homing, pattern formation, and signal transduction). Three organs (lung, heart and bone) of 5 AGA002 mutant mice (age 2x 10 days and 3x 11 days) were analysed by cDNA microarray technology. As reference five mice, 11 days old were used 50% of the chip hybridisations are dye swap experiments.

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Activation of adult human pancreatic ductal and ductal progenitor-like cells requires extracellular matrix protein signaling [scRNA-seq]

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