Intercellular adhesion signaling in stem cell differentiation and cancer

(NSF CBET)

Stelios T. Andreadis Lab

Introduction & Significance

The Stelios Andreadis research group has identified cell-cell adhesion as an important factor determining MSC differentiation.

Specifically, they discovered that Cadherin-11 (CDH11) was necessary for MSC differentiation into SMC through activation of key myogenic transcription factors such as serum response factor (SRF) via the ROCK pathway. Notably, CDH11 was essential for development of SMC containing organs and contractile function in vivo1,2. The lab also discovered that deficiency of CDH11 in fibroblasts also led to impaired extracellular matrix synthesis (ECM) both in vivo and in vitro, severely undermining the tissue’s mechanical properties.

Research Findings

Zoom image: Fig. 1(A): Schematic of proposed mechanism of ECM synthesis following CDH11 engagement. In addition to collagen and elastin, CDH11 is also upregulated, indicating the presence of a positive-feedback loop.  5.1.

Fig. 1(A): Schematic of proposed mechanism of ECM synthesis following CDH11 engagement. In addition to collagen and elastin, CDH11 is also upregulated, indicating the presence of a positive-feedback loop. 

Zoom image: Fig 1(2): Schematic of TMA analysis workflow. (A) Scanned TMA in Aperio; (B), Enlarged one core IHC staining; (C), Pathologist annotation indicating the tumor region; (D) QuPath recognizing the tumor region based on the annotation (E) QuPath identifying individual cells within marked region; (F) QuPath analysis based on the in-built algorithm; (G) Heat map based on analyzed scores. 5.2.

Fig 1(2): Schematic of TMA analysis workflow. (A) Scanned TMA in Aperio; (B), Enlarged one core IHC staining; (C), Pathologist annotation indicating the tumor region; (D) QuPath recognizing the tumor region based on the annotation (E) QuPath identifying individual cells within marked region; (F) QuPath analysis based on the in-built algorithm; (G) Heat map based on analyzed scores.

The results showed that CDH11 engagement activates the TGFβ and ROCK pathways, upregulating key transcription factors MYOCD and MRTF-A/B (Fig. 1A), ultimately leading to elevated ECM synthesis and enhanced tissue biomechanics 3.

The lab also reported that CDH11 interacts with the platelet derived growth factor receptor (PDGFR) and enhances PDGFR sensitivity to PDGF-BB, resulting in enhanced cell proliferation via the AKT pathway. On the other hand, lack of CDH11 in the dermis of Cdh11-/- mice led to severely reduced p-AKT, proliferation (%Ki67+ cells) and number of fibroblasts (Vimentin+) in the wound bed, ultimately leading to significantly delayed wound healing in vivo (t50% healing=8 days in Cdh11-/- vs. 4 days in WT mice). Collectively, our data reveal that CDH11 regulates cell proliferation and wound healing via enhancement of the PDGFb-AKT axis. 

Using a tumor microarray (TMA, available from Roswell Park Comprehensive Cancer Center, RPCCC), the lab screened 209 clinical tumor samples for CDH11 and found that it is highly expressed in multiple tumors, with the highest expression observed in tumors isolated from adrenal gland, brain and breast. In addition, using bioinformatic approaches to analyze The Cancer Genome Atlas (TCGA) publicly available database, we found that CDH11 was expressed at 3-fold higher levels in breast tumors as compared to healthy tissues. Given the interaction with growth factor receptors and other recent data in our laboratory we hypothesize that CDH11 plays a critical role on cancer metastasis.

Future Work

Current and future studies focus on the role of CDH11 in regulating the Wnt pathway in the transition of breast cancer to a metastatic state.

Students of the Project

Post Doc: Pedro Lei, Ph.D.

Graduate Students: Yayu Liu, Ph.D.

Collaborators: Wiam Bshara (Roswell Park Comprehensive Cancer Center)

References

  1. Alimperti, S. & Andreadis, S.T. CDH2 and CDH11 act as regulators of stem cell fate decisions. Stem Cell Res 14, 270-282 (2015).
  2.  Alimperti, S., You, H., George, T., Agarwal, S.K. & Andreadis, S.T. Cadherin-11 regulates both mesenchymal stem cell differentiation into smooth muscle cells and the development of contractile function in vivo. J Cell Sci 127, 2627-2638 (2014).
  3. Row, S., Liu, Y., Alimperti, S., Agarwal, S.K. & Andreadis, S.T. Cadherin-11 is a novel regulator of extracellular matrix synthesis and tissue mechanics. J Cell Sci 129, 2950-2961 (2016).