Publications
Here is a selection of publications where different laminin isoforms were used to create more authentic cell culture systems.
Laminins and cancer stem cells: Partners in crime?
Qin Y., Rodin S., Simonson O.E., Hollande F. Seminars in Cancer Biology, 2016
A review that discusses the role of laminin as a regulator of cancer stem cells, in tumor progression and drug resistance. A growing body of literature suggests that laminins may act as regulators of cancer stem cells, a tumor cell subpopulation that plays an instrumental role in long-term cancer maintenance, metastasis development, and therapeutic resistance. The accumulating evidence in this emerging research area suggests that laminins represent potential therapeutic targets for anti-cancer treatments against cancer stem cells and that they may be used as predictive and prognostic markers to inform clinical management and improve patient survival.
Laminin 521 enhances self-renewal via STAT3 activation and promotes tumor progression in colorectal cancer
Qin Y, Shembrey C, Smith J, Paquet-Fifield S, Behrenbruch C, Beyit LM, Thomson BNJ, Heriot AG, Cao Y, Hollande F.Cancer Lett. 2020
Remodeling of basement membrane proteins contributes to tumor progression towards the metastatic stage. Here, the authors show that one of these proteins, laminin 521 (LN521), promotes colorectal cancer (CRC) cell self-renewal and invasion. siRNA-mediated knockdown of endogenously-produced laminin alpha 5, as well as treatment with neutralizing antibodies against integrin α3β1 and α6β1, were able to reverse the effect of LN521 on self-renewal. Exposure of CRC cells to LN521 enhanced STAT3 phosphorylation, and incubation with STAT3 inhibitors Napabucasin and Stattic were sufficient to block the LN521-driven self-renewal increase. Robust expression of laminin alpha 5 was detected in 7/10 liver metastases tissue sections collected from CRC patients as well as in mouse liver metastasis xenografts, in most cases within areas expressing metastasis cancer stem cell markers such as c-KIT and CD44v6. Finally, retrospective analysis of multiple CRC datasets highlighted the significant association between high LN521 mRNA expression and poor clinical outcome in colorectal cancer patients. Collectively our results indicate that high Laminin 521 expression is a frequent feature of metastatic dissemination in CRC and that it promotes cell invasion and self-renewal, the latter through the engagement of integrin isoforms and activation of STAT3 signaling.
L1CAM defines the regenerative origin of metastasis-initiating cells in colorectal cancer
Ganesh K., Basnet H., Kaygusuz Y., Laughney A.M., He L., Sharma R., O’Rourke K.P., Reuter V.P., Huang Y.-H., Turkekul M., Er E.E., Masilionis I., Manova-Todorova K., Weiser M.R., Saltz L.B., Garcia-Aguilar J., Koche R., Lowe S.W., Pe’er D., Shia J., Massagué J.Nature Cancer, 2020
The authors show that L1CAM+ cells in human colorectal cancer (CRC) have metastasis-initiating capacity, and they define their relationship to tissue regeneration. By using recombinant L1CAM extracellular domain and basement membrane components, they confirmed that L1CAM bound heterophilically to laminins known to be expressed in the intestinal and endothelial cell basement membranes in addition to exhibiting homophilic interaction with L1CAM itself. L1CAM knockdown inhibited the ability of CRC organoid-derived cells to bind to laminin-coated plates. Together, these data suggest that L1CAM enables the adhesion of metastasis-initiating cells to laminin-rich basement membranes, which is required for metastasis and organoid growth.
Laminin-421 produced by lymphatic endothelial cells induces chemotaxis for human melanoma cells
Saito N., Hamada J., Furukawa H., Tsutsumida A., Oyama A., Funayama E., Saito A., Tsuji T., Tada M., Moriuchi T., Yamamoto Y.Pigment Cell Melanoma Res., 2009
Here, the authors investigate the molecular mechanism of lymphatic metastasis. They examined the influence of interactions between normal lymphatic endothelial cells (LECs) and melanoma cells on cell migration. LEC conditioned medium (LEC-CM) contained chemotactic and chemokinetic activities for human melanoma cell lines. The chemotactic activity of LEC-CM was abolished by immunodepletion with anti-laminin-1 antibody. And immunoprecipitation and Western blot analyses revealed that LEC-CM contained laminin a4 and 5, b1 and 2, and c1, corresponding to isoforms -521, -511, -421 and -411. When melanoma C8161 cells were treated with function-blocking antibodies to integrin a3 or a6, their chemotactic responses to LEC-CM were markedly reduced. Furthermore, the knock-down of tetraspanin CD151 weakened the chemotactic responses of C8161 and MeWo cells to LEC-CM. These data suggest that laminin secreted by LEC possibly facilitates lymphatic metastasis through the induction of chemotaxis of melanoma cells.
A laminin 511 matrix is regulated by TAZ and functions as the ligand for the a6Bb1 integrin to sustain breast cancer stem cells
Chang C., Lal Goel H., Gao H., Pursell B., Shultz L.D., Greiner D.L., Ingerpuu S., Patarroyo M., Cao S., Lim E., Mao J., Kulju McKee K., Yurchenco P.D., Mercurio A.M.Research communication, 2015
One of the first papers that highlighted the importance of ECM proteins in 2D breast cancer stem cell culture. Shows that laminin-511 is an acritical niche component for breast cancer stem cells. Breast cancer stem cells produce a laminin-511 matrix that functions as the ligand for the a6Bb1 integrin to promote self-renewal and tumor initiation. The authors observed that TAZ regulates the transcription of the a5 subunit of laminin-511 and the formation of a laminin-511 matrix. These data establish a positive feedback loop involving TAZ and laminin-511 that contributes to stemness in breast cancer. They see down-regulation of the laminin B2 chain.
ARNT-dependent HIF-2 transcriptional activity is not sufficient to regulate downstream target genes in neuroblastoma
Persson C.U., von Stedingk K., Fredlund E., Bexell D., Påhlman S., Wigerup C. Mohlin S.Experimental cell research, 2020
Hypoxia-inducible factor (HIF)-2α associates with poor outcomes in neuroblastoma and glioblastoma, and gain-of-function mutations in the EPAS1gene (encoding HIF-2α) have been reported in paragangliomas and pheochromocytomas. Specific targeting of a druggable hydrophobic pocket in the HIF-2αPAS-B domain with PT2385 has demonstrated promising clinical results for clear cell renal cell carcinoma (ccRCC). Here, the authors investigated the effect of PT2385-mediated inhibition of ARNT dependent HIF-2 activity. Neuroblastoma patient-derived xenograft (PDX) cells cultured on Biolaminin 521 were treated with PT2385 and analyzed for HIF-2-dependent gene expression, HIF activity, HIF-2αprotein localization, response to chemotherapy and orthotopic tumor growth in vivo. The authors detected high levels of HIF-2α protein in perivascular niches in neuroblastoma PDXs in vivo and at oxygenated conditions in PDX-derived cell cultures in vitro, particularly in the cytoplasmic fraction. Nuclear HIF-2αexpression was reduced following PT2385 treatment, but surprisingly, virtually no effects on tumor growth in vivo or expression of canonical HIF downstream target genes in vitro were observed. RNA sequencing of PT2385-treated PDX cells revealed a virtually unaffected transcriptome. Treatment with PT2385 did not affect cellular response to chemotherapy. In contrast, HIF-2αprotein knockdown resulted in profound downregulation of target genes. The lack of effect from PT2385 treatment in combination with high cytoplasmic HIF-2αexpressionat normoxia suggests that HIF-2α has additional roles than acting as an ARNT dependent transcription factor. It is important to further unravel the conditions at which HIF-2αhas transcriptional and non-transcriptional roles in neuroblastoma.