Upregulation of Extracellular Matrix Internalization Promotes Invasive Migration in Cancer Cells

Core Concepts

Increased internalization and degradation of extracellular matrix (ECM) components, mediated by the α2β1 integrin/p38 MAPK signaling axis, facilitates invasive migration of breast, ovarian, and pancreatic cancer cells.

Abstract

The study investigates the mechanisms underlying the internalization of extracellular matrix (ECM) components and its impact on cancer cell invasion and metastasis. The key findings are:

1. ECM internalization and degradation are upregulated in invasive breast cancer cells compared to normal mammary epithelial cells. The ECM is trafficked through early endosomes and delivered to lysosomes for degradation.

2. A kinase and phosphatase screen identified MAP3K1, MAPK11 (p38β), and PPP2R1A as novel regulators of ECM macropinocytosis, which is mediated by the α2β1 integrin.

3. Disruption of the α2β1 integrin/p38 MAPK signaling axis impaired ECM internalization and significantly reduced the invasive migration and 3D invasion of breast, ovarian, and pancreatic cancer cells.

4. Expression of α2 integrin, β1 integrin, and MAP3K1 was significantly upregulated in pancreatic tumors and correlated with poor prognosis in pancreatic cancer patients.

5. Chemotherapy-resistant breast tumors showed higher mRNA levels of MAP3K1, MAPK11, PPP2R1A, and α2 integrin, suggesting a link between ECM internalization, therapy resistance, and metastatic dissemination.

The study identifies a novel signaling pathway linking ECM macropinocytosis, degradation, and invasive migration in different cancer types, which could be targeted for the development of new therapeutic interventions to prevent metastatic spread.

Stats

The extracellular matrix (ECM) internalisation was upregulated in primary breast cancer cells (PyMT#1) compared to normal mammary epithelial cells (NMuMG).
Downregulation of β1 integrin significantly reduced Matrigel internalisation in MDA-MB-231 cells.
Inhibition or downregulation of α2 integrin significantly decreased the uptake of collagen I-rich matrices in MDA-MB-231, A2780-Rab25, YEJ P and SW1990 cells.
Knockdown of MAP3K1, MAPK11 or PPP2R1A significantly reduced ECM uptake and the internal pool of α2 integrin in MDA-MB-231 cells.
Pharmacological inhibition or siRNA-mediated downregulation of ECM uptake regulators reduced the velocity and directionality of migrating MDA-MB-231 and A2780-Rab25 cells.
α2 integrin expression was upregulated in mouse mammary cancer tissues compared to normal mammary glands.
MAP3K1, MAPK11, PPP2R1A and α2 integrin expression were higher in chemotherapy-resistant breast tumors.
α2 integrin, β1 integrin and MAP3K1 expression were significantly upregulated in pancreatic tumors and correlated with poor prognosis in pancreatic cancer patients.

Quotes

"ECM internalisation and degradation is upregulated in invasive breast cancer."
"α2β1 integrin is required for ECM internalisation in different cancer types."
"MAP3K1, MAPK11 and PPP2R1A regulate macropinocytosis of ECM-bound α2β1 integrin."
"Disruption of the α2β1 integrin/p38 MAPK signaling axis impaired ECM internalization and significantly reduced the invasive migration and 3D invasion of breast, ovarian, and pancreatic cancer cells."
"Expression of α2 integrin, β1 integrin, and MAP3K1 was significantly upregulated in pancreatic tumors and correlated with poor prognosis in pancreatic cancer patients."

Key Insights Distilled From

Internalisation of integrin-bound extracellular matrix modulates invasive carcinoma cell migration

by Llanses Mart... at www.biorxiv.org 01-14-2024

https://www.biorxiv.org/content/10.1101/2024.01.11.575153v1

Deeper Inquiries

How might the stress response during cancer dissemination contribute to the upregulation of ECM internalization and invasive migration?

The stress response during cancer dissemination can contribute to the upregulation of ECM internalization and invasive migration through various mechanisms. Firstly, the stress response in cancer cells can lead to the activation of signaling pathways, such as the p38 MAPK pathway, which has been shown to regulate ECM internalization. Stress-induced activation of p38 MAPK can promote the internalization of ECM-bound integrins, such as α2β1 integrin, leading to increased ECM uptake and degradation. This process can facilitate invasive migration by providing cancer cells with the necessary nutrients and signaling cues from the ECM to support their migration and invasion into surrounding tissues.
Additionally, the stress response can induce changes in the cytoskeleton and cell adhesion molecules, which are essential for cell migration. Stress-induced alterations in the cytoskeleton can enhance the formation of membrane protrusions and invadopodia, structures that are crucial for cancer cell invasion. These changes can promote the internalization of ECM components and facilitate the remodeling of the ECM to create pathways for cancer cell migration. Moreover, the stress response can modulate the expression and activity of ECM receptors, such as integrins, which play a key role in ECM internalization and cell migration. Upregulation of integrins, particularly α2β1 integrin, can enhance ECM internalization and promote invasive migration of cancer cells.
Overall, the stress response during cancer dissemination can create a microenvironment that supports ECM internalization and invasive migration by activating signaling pathways, altering the cytoskeleton, and modulating the expression of ECM receptors.

How might the stress response during cancer dissemination contribute to the upregulation of ECM internalization and invasive migration?

Chemotherapy resistance in breast cancer is linked to increased expression of ECM internalization regulators through several potential mechanisms. Firstly, chemotherapy treatment can induce cellular stress and activate survival pathways in cancer cells, leading to the upregulation of ECM internalization regulators. The stress response triggered by chemotherapy can promote the expression of proteins involved in ECM internalization, such as MAP3K1, MAPK11, PPP2R1A, and α2 integrin, to enhance cancer cell survival and resistance to treatment.
Moreover, chemotherapy-resistant cancer cells often exhibit alterations in their interactions with the ECM, including increased ECM internalization and degradation. The upregulation of ECM internalization regulators can provide chemotherapy-resistant cells with a survival advantage by promoting the uptake of nutrients and growth factors from the ECM, thereby supporting their proliferation and survival in the presence of chemotherapy drugs. Additionally, the increased expression of ECM internalization regulators can enhance the invasive migration of chemotherapy-resistant cancer cells, allowing them to escape the cytotoxic effects of chemotherapy and metastasize to distant sites.
Furthermore, the dysregulation of ECM internalization pathways in chemotherapy-resistant breast cancer cells can contribute to the development of a more aggressive and invasive phenotype, making them less responsive to standard chemotherapy treatments. Targeting the regulators of ECM internalization in chemotherapy-resistant breast cancer cells may represent a promising strategy to overcome drug resistance and improve treatment outcomes.

Could targeting the α2β1 integrin/p38 MAPK signaling axis be a viable therapeutic strategy to prevent metastatic spread in multiple cancer types, and how might this be combined with existing treatments?

Targeting the α2β1 integrin/p38 MAPK signaling axis could indeed be a viable therapeutic strategy to prevent metastatic spread in multiple cancer types. The α2β1 integrin/p38 MAPK signaling axis plays a crucial role in regulating ECM internalization, invasive migration, and tumor progression in various cancer types, including breast, ovarian, and pancreatic cancer. Inhibition of this signaling axis can disrupt the internalization of ECM components, impair invasive migration, and inhibit metastatic dissemination of cancer cells.
Combining the targeting of the α2β1 integrin/p38 MAPK signaling axis with existing treatments, such as chemotherapy or targeted therapies, could enhance the efficacy of cancer treatment and prevent metastatic spread. For example, combining inhibitors of α2β1 integrin or p38 MAPK with standard chemotherapy drugs could potentially overcome chemotherapy resistance in breast cancer and other cancer types. By blocking the signaling pathways that promote ECM internalization and invasive migration, this combination therapy could inhibit the spread of cancer cells to distant organs and improve patient outcomes.
Furthermore, targeting the α2β1 integrin/p38 MAPK signaling axis may have synergistic effects with other targeted therapies that disrupt specific pathways involved in cancer progression. For instance, combining inhibitors of the α2β1 integrin/p38 MAPK axis with inhibitors of growth factor receptors or angiogenesis pathways could provide a comprehensive approach to inhibit tumor growth, invasion, and metastasis. Overall, targeting the α2β1 integrin/p38 MAPK signaling axis in combination with existing treatments holds promise as a therapeutic strategy to prevent metastatic spread and improve the outcomes of cancer patients.