Expression/Mechanism of ROR1 in healthy tissue

Question

ROR1 is currently under investigation as a therapeutic target for cancer (1). A number of studies show different cancers may have their metastatic potential reduced, or become apoptotic through targeting or abrogation of ROR1 (1-3). ROR1 itself is show to have a number interactions (either through crosstalk or interaction) with some known tumorigenic markers; these include c-Met, PI3K, Akt, Wnt5a, EGF, c-Src (4-7). In terms of metastatic potential, interactions with vimentin, Snail/Slug, cadherins, ß-catenin, and CXCR4/CXCL12 were also identified (1, 8). Some of these are via expression of CREB. In terms of ROR1 is tissue, abnormalities that lead to death were noted in newborn mice that has ROR1 knocked down (9). A notable mechanism for ROR1 in development was in neuroprogenitor cells in which ROR1 regulation status determined whether these cells differentiated into neurons or not (10). It's also found that neural, heart, lung and kidney tissue in adults express some form or another of ROR1 (11). More recent studies suggest ROR1 downmodulation may present toxicity for some subsets of normal tissues (12).

The question, now: Are there any empirical studies that illuminate the potential mechanism of ROR1 in healthy, adult tissues? This is from a treatment toxicity standpoint, since the subsets of affected cells seem to be rather slim. I can understand why the effect on metastatic potential can be significant from the fetal neural cortex development (the need to migrate the neurons into position). We also see a truncated version of ROR1 in some instances. If anyone can shed some light, thank you in advance!

References

1. Cui B. et al. Targeting ROR1 inhibits epithelial-mesenchymal transition and metastasis. Cancer. Res. 73, 3649–3660 (2012).
2. Hojjat-Farsangi, M., Ghaemimanesh, F., Daneshmanesh, A. H., Bayat, A. A., Mahmoudian, J., Jeddi-Tehrani, M., … Mellstedt, H. (2013). Inhibition of the Receptor Tyrosine Kinase ROR1 by Anti-ROR1 Monoclonal Antibodies and siRNA Induced Apoptosis of Melanoma Cells. PLoS ONE, 8. doi:10.1371/journal.pone.0061167
3. Daneshmanesh AH, Hojjat-Farsangi M, Sandin A, Khan AS, Moshfegh A, et al.. (2012) Monoclonal Antibody Against ROR1 In Chronic Lymphocytic Leukemia Cells Induced Apoptosis Via PI3-kinase/AKT/CREB pathway. 54th American Society of hematology (ASH), Atlanta, USA, 8–11 December.
4. T. Yamaguchi, K. Yanagisawa, R. Sugiyama, Y. Hosono, Y. Shimada, C. Arima, S. Kato, S. Tomida, M. Suzuki, H. Osada, T. Takahashi. NKX2-1/TITF1/TTF-1-induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma. Cancer Cell, 21 (2012), pp. 348–361
5. Fukuda T, Chen L, Endo T, Tang L, Lu D, Castro JE, Widhopf GF, II, Rassenti LZ, Cantwell MJ, Prussak CE, et al. Antisera induced by infusions of autologous Ad-CD154-leukemia B cells identify ROR1 as an oncofetal antigen and receptor for Wnt5a. Proc Natl Acad Sci USA. 2008;105:3047–3052. doi: 10.1073/pnas.0712148105.
6. Gentile A, Lazzari L, Benvenuti S, Trusolino L, Comoglio PM. Ror1 is a pseudokinase that is crucial for Met-driven tumorigenesis. Cancer Res 2011;71:3132–41.
7. Zhang S, Chen L, Cui B, Chuang HY, Yu J, Wang-Rodriguez J, et al. ROR1 is expressed in human breast cancer and associated with enhanced tumor-cell growth. PLoS ONE 2012;7:e31127.
8. Teicher BA, Fricker SP. CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin CancerRes. 2010;16(11):2927-31.
9. Nomi M, Oishi I, Kani S, Suzuki H, Matsuda T, Yoda A, et al. Loss of mRor1 enhances the heart and skeletal abnormalities in mRor2-deficient mice: redundant and pleiotropic functions of mRor1 and mRor2 receptor tyrosine kinases. Mol Cell Biol 2001;21:8329–35.
10. Endo M, Doi R, Nishita M, Minami Y. Ror family receptor tyrosine kinases regulate the maintenance of neural progenitor cells in the developing neocortex. J Cell Sci 2012;125:2017–29.
11. Reddy UR, Phatak S, Pleasure D. Human neural tissues express a truncated Ror1 receptor tyrosine kinase, lacking both extracellular and transmembrane domains. Oncogene 1996;13:1555–9.
12. Linked in text.

Answer 1

Examining the literature it'd seem that the ROR pathways incl. ROR1 and ROR2 are critical for developing tissues in the majority of cases. We also see relevance in the expression of ROR1/2, more specifically ROR2, in cases where taxic cell types are required to migrate, branch, etc. Most of the literature determines much of this occurs through a noncanonical Wnt signaling pathway.

Wnt5a–Ror–Dishevelled signaling constitutes a core developmental pathway that controls tissue morphogenesis

Ror2 Receptor Mediates Wnt11 Ligand Signaling and Affects Convergence and Extension Movements in Zebrafish

Ror2 regulates branching, differentiation, and actin-cytoskeletal dynamics within the mammary epithelium

Notwithstanding the abnormalities we see in neonates with knocked down ROR, is it wrong to assume we'd see developmental defects of branching tissues in developing (or juvenile) organisms such as lung, mammary, neural, glandular tissue, etc.? Some data in that respect would be interesting, but it's also illuminating given the presence of ROR in cancer metastasis and EMT events.